Patients undergoing "curative" cancer surgery occasionally develop distant metastases faster and in greater volume than would be expected from the natural history of their resected tumors. In many animal models surgical stress increases both the number and growth rate of metastases relative to unstressed controls. The object of this study is to determine the impact of surgery on host immune protection against metastases. Mechanisms harmed by surgery will be identified; methods to reverse their surgically induced impairment will be explored. Natural killer cells (NKC) play a crucial role in surveillance and clearance of circulating tumor cells, thereby helping prevent metastases. NKC cytotoxicity is decreased by as much as 68% one day after the application of surgical stress (amputation) in a mouse model using an in vitro 51Cr release assay. Other immune factors are also important in defense against malignancy. Primary and secondary antibody response (as measured by hemagglutination microtiter techniques) and the blastogenic transformation of lymphocytes after mitogen stimulation with PHA and LPS will be studied in control, surgically stressed, and tumor bearing surgically stressed for mice. An in vivo model of surgical stress-induced metastasis is being developed using mice first amputated and then one day later foot pad inoculated with 500,000 Lewis lung tumor cells. The observed surgical impairment of NKC cytotoxicity, and the potential impairment of antibody formation and lymphoblastogenesis may be preventable by preoperative treatment with the biologic response modifier tuftsin. Likewise, preoperative tuftsin may be successful in protecting against stress-induced metastases in vivo. Ultimately, these animal studies may suggest a possible explanation and solution for the dilemma of surgically induced metastasis--a possibility that has direct human application.